The anthracycline antibiotics include some of the most therapeutically useful and promising agents for the treatment of cancer. The proposed research is part of a continuing effort to develop synthetic methods for the efficient and practical preparation of these important compounds. A route for unified total syntheses of all anthracyclinones with a 9-hydroxy-9-alkyl-10-carbomethoxy-substituted A-ring will be developed. The use of a magnesium ion mediated intramolecular aldol cyclization of an optically active ester will be employed to effect direct chiral synthesis of these anthracyclinones. Specific aglycons which will be prepared are aklavinone (31), pyrromycinone (3n), Epsilon-rhodomycinone (3p), and Epsilon-isorhodomycinone (3r). The intramolecular ene reaction which has been used to accomplish stereospecific total synthesis of anthracyclinones with cis-7,9-dihydroxylation and a 9-alkyl substituent will be developed as a method for preparation of the corresponding 9-acetyl compounds. Asymmetric epoxidation of an olefinic alcohol intermediate will be employed to effect chiral synthesis of this group. Daunomycinone, 6-deoxydaunomycinone and 11-deoxydaunomycinone will be prepared. The ene reaction is also a key feature of the proposed stereospecific total synthesis of pillaromycin, an anthracycline antibiotic with two saturated rings. The development of procedures for preparation of racemic and chiral phthalide-sulfone-substituted epoxybenzoxocins will be continued. These compounds will be employed to accomplish convergent syntheses of nogalamycin and 7-con-0-methyl nogarol. Simple analogs of epoxybenzoxocins have shown anticancer activity and other analogs will be prepared in an effort to enhance this effect. These studies will provide methodology essential for total syntheses of veneomycin, chromocyclomycin, granaticin, and fredricamycin A, syntheses of which are long-range objectives of our program.